This application from the University of California at San Diego (UCSD) for a SCOR on "The Molecular Physiology of Heart Failure" will align powerful analytic methods with relevant research and administrative experience in a research plan which offers a novel, comprehensive and transferrable approach tot he study of heart failure. Our overall goal is to improve understanding of the molecular, physiological, and ultrastructural bases for adaptive and maladaptive signaling mechanisms in heart failure. The research strategies include: the application of mouse genetics to identify the signaling pathways which mediate cardiac dysfunction; identification and cloning of candidate genes for hypertrophy and heart failure using advanced molecular approaches for targeting their expression in cultured myocardial cells; the development of novel genetic-based animal models of ventricular hypertrophy and failure utilizing promoters that can target expression of a given transgene in to the cardiac ventricles; in vivo phenotypic characterization of transgenic murine models harboring candidate genes using newly developed quantitative microangiographic methods; the application of these angiographic methods to study the effects of growth factors in heart failure; studies on the genetic bases for familial dilated cardiomyopathy in well-defined kindreds using linkage analysis supplemented by the new molecular technique of representational difference analysis; the alignment of physiologic, biochemical and molecular techniques to study the bases for maladaptive effects of adrenergic stimulation at the receptor and post-receptor levels in animal models and human tissue; physiologic studies on the cardiac effects of abnormal force-frequency relations in experimental models and in patients with heart failure and of the recently- discovered key role of adrenergic control of force-frequency relations; use of novel electrophysiologic methods to study the Ca2+ transport system, including the sarcoplasmic reticular Ca2+ ATPase pump and the Na+/Ca2+ exchanger in isolated cells from failing human hearts and in experimental models. The themes of genetic and molecular signaling in myocardial hypertrophy and failure, genetic abnormalities in clinical heart failure, maladaptive beta-adrenergic signaling and the influence of Ca2+ transport proteins on myocardial contraction will be investigated at several levels of system complexity, including the molecular, cellular, intact animal, and man.